US2009234024A1PendingUtilityA1
Estrogenic compounds, process for their production and pharmaceutical uses thereof
Est. expiryFeb 4, 2028(~1.6 yrs left)· nominal 20-yr term from priority
A61P 5/30C07C 323/16C07C 2602/24A61P 15/18A61P 15/00C07C 37/20C07B 2200/07C07C 39/42C07C 39/17C07C 39/23
55
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Claims
Abstract
The present invention provides new estrogenic compounds of the general formula in which the substituents have the meanings that are explained in more detail in the description, and pharmaceutical compositions containing them. The compounds of the invention are useful, for example, in hormone replacement therapies (HRT/ERT) and as contraceptives and estrogenic hormone therapies. Also provided is a process for synthesizing the compounds of the invention.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I, or a pharmaceutically acceptable salt, ester or solvate thereof,
where
R 1 is H, halogen or CH 3 ;
R 2 is H, halogen or CH 3 ;
R 4 is H, halogen or CH 3 ;
R 5 is H, halogen, CF 3 , C 1 -C 5 alkyl, CH 2 OH, CH 2 OAc, CH 2 CH 2 OH, CH 2 CH 2 OAc, CH 2 -aryl, CH 2 -heteroaryl, CH═CH 2 , CH 2 CH 2 SCH 3 , CH 2 CH 2 SC 2 H 5 , CH 2 CH 2 SCH 2 Ar, CH 2 CH 2 SCH 2 -heteroaryl, OH, OCH 3 , OC 2 H 5 , OCH 2 Ar, OCH 2 -heteroaryl, OAc, SCH 3 , SC 2 H 5 , SCH 2 Ar, SCH 2 -heteroaryl, SOCH 3 , SOC 2 H 5 , SOCH 2 Ar, SOCH 2 -heteroaryl, SO 2 CH 3 , SO 2 C 2 H 5 , SO 2 CH 2 Ar, SO 2 CH 2 -heteroaryl, CN, CHO, COCH 3 , COC 2 H 5 , CO 2 H, CO 2 CH 3 , CO 2 C 2 H 5 , CO 2 CH 2 Ar, CO 2 CH 2 -heteroaryl, CONH 2 , CON(CH 3 ) 2 , CON(CH 2 ) 4 , CON(CH 2 ) 5 , or NO 2 ;
R 9 is absent, H or OH; and
R 17 is H or C 2 H.
2 . The compound of claim 1 which has the structure of Formula Ia:
wherein R 9 is H or OH.
3 . The compound of claim 1 , wherein
R 1 is H, F or CH 3 ; R 2 is H or F; R 4 is H or F; R 5 is H, F, Cl, CF 3 , CH 3 , C 2 H 5 , nC 3 H 7 , iC 3 H 7 , CH 2 OH, CH 2 OAc, CH 2 CH 2 OH, CH 2 CH 2 OAc, CH 2 -aryl, CH 2 -heteroaryl, CH═CH 2 , CH 2 CH 2 SCH 3 , CH 2 CH 2 SC 2 H 5 , CH 2 CH 2 SCH 2 Ar, CH 2 CH 2 SCH 2 -heteroaryl, OH, OCH 3 , OC 2 H 5 , OCH 2 Ar, OCH 2 -heteroaryl, OAc, SCH 3 , SC 2 H 5 , SCH 2 Ar, SCH 2 -heteroaryl, SOCH 3 , SOC 2 H 5 , SOCH 2 Ar, SOCH 2 -heteroaryl, SO 2 CH 3 , SO 2 C 2 H 5 , SO 2 CH 2 Ar, SO 2 CH 2 -heteroaryl, CN, CHO, COCH 3 COC 2 H 5 , CO 2 H, CO 2 CH 3 , CO 2 C 2 H 5 , CO 2 CH 2 Ar, CO 2 CH 2 -heteroaryl, CONH 2 , CON(CH 3 ) 2 , CON(CH 2 ) 4 , CON(CH 2 ) 5 or NO 2 ; R 9 =H or OH; and R 17 is H or ethynyl.
4 . The compound of claim 3 , wherein R 2 and R 4 are H.
5 . The compound of claim 3 , wherein R 5 is H, F, Cl or CH 3 .
6 . The compound of claim 1 , wherein said halogen is F or Cl.
7 . The compound of claim 1 , wherein at least one of R 1 , R 2 , R 4 , and R 5 is not H.
8 . The compound of claim 3 , wherein R 2 , R 4 and R 5 are F, and R 1 , R 9 and R 17 are H.
9 . The compound of claim 3 , wherein R 1 , R 2 , R 4 , R 5 , R 9 and R 17 are each H.
10 . The compound of claim 2 , wherein R 1 , R 2 , R 4 , R 9 and R 17 are each H and R 5 is F or Cl.
11 . A composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient or diluent.
12 . The composition of claim 11 , wherein
R 1 is H, F or CH 3 ; R 2 is H or F; R 4 is H or F; R 5 is H, F, Cl, CF 3 , CH 3 , C 2 H 5 , nC 3 H 7 , iC 3 H 7 , CH 2 OH, CH 2 OAc, CH 2 CH 2 OH, CH 2 CH 2 OAc, CH 2 -aryl, CH 2 -heteroaryl, CH═CH 2 , CH 2 CH 2 SCH 3 , CH 2 CH 2 SC 2 H 5 , CH 2 CH 2 SCH 2 Ar, CH 2 CH 2 SCH 2 -heteroaryl, OH, OCH 3 , OC 2 H 5 , OCH 2 Ar, OCH 2 -heteroaryl, OAc, SCH 3 , SC 2 H 5 , SCH 2 Ar, SCH 2 -heteroaryl, SOCH 3 , SOC 2 H 5 , SOCH 2 Ar, SOCH 2 -heteroaryl, SO 2 CH 3 , SO 2 C 2 H 5 , SO 2 CH 2 Ar, SO 2 CH 2 -heteroaryl, CN, CHO, COCH 3 COC 2 H 5 , CO 2 H, CO 2 CH 3 , CO 2 C 2 H 5 , CO 2 CH 2 Ar, CO 2 CH 2 -heteroaryl, CONH 2 , CON(CH 3 ) 2 , CON(CH 2 ) 4 , CON(CH 2 ) 5 or NO 2 ; R 9 is H or OH; and R 17 is H or ethynyl.
13 . The composition of claim 12 , wherein R 2 and R 4 are H.
14 . The composition of claim 12 , wherein R 5 is H, F, Cl or CH 3 .
15 . The composition of claim 11 , wherein said halogen is F or Cl.
16 . The composition of claim 11 , wherein at least one of R 1 , R 2 , R 4 , and R 5 is not H.
17 . The composition of claim 12 , wherein R 2 , R 4 and R 5 are F, and R 1 , R 9 and R 17 are H.
18 . The composition of claim 12 , wherein R 1 , R 2 , R 4 , R 5 , R 9 and R 17 are each H.
19 . The composition of claim 12 , wherein R 1 , R 2 , R 4 , R 9 and R 17 are each H and R 5 is F or Cl.
20 . The composition of claim 11 , for use in treating or preventing a disorder or disease related to estrogen functioning.
21 . The composition of claim 11 , in a form for oral, nasal, parenteral, topical, transdermal, rectal, sublingual, intramuscular, subcutaneous, or intravenous administration.
22 . The composition of claim 11 , wherein said composition is in the form of a capsule, caplet or tablet.
23 . A method for methods for treating or preventing a disorder or disease related to estrogen functioning in a subject, comprising administering to said subject an effective amount of a compound according to claim 1 .
24 . The method of claim 23 , wherein said method is for hormone replacement therapy.
25 . The method of claim 23 , wherein said method is for estrogenic hormone therapy.
26 . A method for contraception of a female subject, comprising administering to said subject an effective amount of a compound according to claim 1 .
27 . A process for synthesizing a compound of claim 1 comprising coupling an enantiomerically pure ketone of Formula II with a lithium compound of Formula III,
where R and R 6 are independently H, alkyl or a protecting group and R 1 , R 2 , R 4 , R 5 and R 17 have the meaning defined above in relation to Formula I.
28 . The compound of claim 2 , wherein
R 1 is H, F or CH 3 ; R 2 is H or F; R 4 is H or F; R 5 is H, F, Cl, CF 3 , CH 3 , C 2 H 5 , nC 3 H 7 , iC 3 H 7 , CH 2 OH, CH 2 OAc, CH 2 CH 2 OH, CH 2 CH 2 OAc, CH 2 -aryl, CH 2 -heteroaryl, CH═CH 2 , CH 2 CH 2 SCH 3 , CH 2 CH 2 SC 2 H 5 , CH 2 CH 2 SCH 2 Ar, CH 2 CH 2 SCH 2 -heteroaryl, OH, OCH 3 , OC 2 H 5 , OCH 2 Ar, OCH 2 -heteroaryl, OAc, SCH 3 , SC 2 H 5 , SCH 2 Ar, SCH 2 -heteroaryl, SOCH 3 , SOC 2 H 5 , SOCH 2 Ar, SOCH 2 -heteroaryl, SO 2 CH 3 , SO 2 C 2 H 5 , SO 2 CH 2 Ar, SO 2 CH 2 -heteroaryl, CN, CHO, COCH 3 COC 2 H 5 , CO 2 H, CO 2 CH 3 , CO 2 C 2 H 5 , CO 2 CH 2 Ar, CO 2 CH 2 -heteroaryl, CONH 2 , CON(CH 3 ) 2 , CON(CH 2 ) 4 , CON(CH 2 ) 5 or NO 2 ; R 9 is H or OH; and R 17 is H or ethynyl.
29 . The compound of claim 28 , wherein R 2 and R 4 are H.
30 . The compound of claim 28 , wherein R 5 is H, F, Cl or CH 3 .
31 . The compound of claim 2 , wherein said halogen is F or Cl.
32 . The compound of claim 2 , wherein at least one of R 1 , R 2 , R 4 , and R 5 is not H.
33 . The compound of claim 28 , wherein R 2 , R 4 and R 5 are F, and R 1 , R 9 and R 17 are H.
34 . The compound of claim 28 , wherein R 1 , R 2 , R 4 , R 5 , R 9 and R 17 are each H.
35 . A composition comprising a compound according to claim 2 and a pharmaceutically acceptable excipient or diluent.
36 . The composition of claim 35 , wherein
R 1 is H, F or CH 3 ; R 2 is H or F; R 4 is H or F; R 5 is H, F, Cl, CF 3 , CH 3 , C 2 H 5 , nC 3 H 7 , iC 3 H 7 , CH 2 OH, CH 2 OAc, CH 2 CH 2 OH, CH 2 CH 2 OAc, CH 2 -aryl, CH 2 -heteroaryl, CH═CH 2 , CH 2 CH 2 SCH 3 , CH 2 CH 2 SC 2 H 5 , CH 2 CH 2 SCH 2 Ar, CH 2 CH 2 SCH 2 -heteroaryl, OH, OCH 3 , OC 2 H 5 , OCH 2 Ar, OCH 2 -heteroaryl, OAc, SCH 3 , SC 2 H 5 , SCH 2 Ar, SCH 2 -heteroaryl, SOCH 3 , SOC 2 H 5 , SOCH 2 Ar, SOCH 2 -heteroaryl, SO 2 CH 3 , SO 2 C 2 H 5 , SO 2 CH 2 Ar, SO 2 CH 2 -heteroaryl, CN, CHO, COCH 3 COC 2 H 5 , CO 2 H, CO 2 CH 3 , CO 2 C 2 H 5 , CO 2 CH 2 Ar, CO 2 CH 2 -heteroaryl, CONH 2 , CON(CH 3 ) 2 , CON(CH 2 ) 4 , CON(CH 2 ) 5 or NO 2 ; R 9 is H or OH; and R 17 is H or ethynyl.
37 . The composition of claim 36 , wherein R 2 and R 4 are H.
38 . The composition of claim 36 , wherein R 5 is H, F, Cl or CH 3 .
39 . The composition of claim 35 , wherein said halogen is F or Cl.
40 . The composition of claim 35 , wherein at least one of R 1 , R 2 , R 4 , and R 5 is not H.
41 . The composition of claim 36 , wherein R 2 , R 4 and R 5 are F, and R 1 , R 9 and R 17 are H.
42 . The composition of claim 36 , wherein R 1 , R 2 , R 4 , R 5 , R 9 and R 17 are each H.
43 . The composition of claim 36 , wherein R 1 , R 2 , R 4 , R 9 and R 17 are each H and R 5 is F or Cl.
44 . The composition of claim 35 , for use in treating or preventing a disorder or disease related to estrogen functioning.
45 . The composition of claim 35 , in a form for oral, nasal, parenteral, topical, transdermal, rectal, sublingual, intramuscular, subcutaneous, or intravenous administration.
46 . The composition of claim 35 , wherein said composition is in the form of a capsule, caplet or tablet.
47 . A method for methods for treating or preventing a disorder or disease related to estrogen functioning in a subject, comprising administering to said subject an effective amount of a compound according to claim 2 .
48 . The method of claim 47 , wherein said method is for hormone replacement therapy.
49 . The method of claim 47 , wherein said method is for estrogenic hormone therapy.
50 . A method for contraception of a female subject, comprising administering to said subject an effective amount of a compound according to claim 2 .
51 . A process for synthesizing a compound of claim 2 comprising coupling an enantiomerically pure ketone of Formula II with a lithium compound of Formula III,
where R and R 6 are independently H, alkyl or a protecting group and R 1 , R 2 , R 4 , R 5 and R 17 have the meaning defined above in relation to Formula I.Cited by (0)
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